Drug-induced exanthems

doi:10.1016/j.tox.2004.12.023

Toxicology

Volume 209, Issue 2, 15 April 2005, Pages 131-134

https://doi.org/10.1016/j.tox.2004.12.023 Get rights and content

Abstract

Cutaneous adverse reactions to drugs can comprise a broad spectrum of clinical and histopathological features. Recent evidence from immunohistological and functional studies of drug-reactive T cells suggest that distinct T-cell functions may be responsible for this broad spectrum of different clinical reactions. Maculopapular exanthems represent the most commonly encountered cutaneous drug eruption.

Previous studies on maculopapular exanthems indicate that drug-specific CD4+ T cells expressing cytotoxic granule proteins such as perforin and granzyme B are critically involved in killing activated keratinocytes. These cells are particularly found at the dermo-epidermal junction and may contribute to the generation of vacuolar alteration and destruction of basal keratinocytes, which are typical found in drug-induced maculopapular exanthems. In contrast to maculopapular exanthems, the preferential activation of drug-specific cytotoxic CD8+ T cells may lead to more severe reactions like bullous drug eruptions. Furthermore, activation of drug-specific T with distinct cytokine and chemokines profiles may also explain the different clinical features of drug-induced exanthems. IL-5 and eotaxin are upregulated in maculopapular exanthems and explain the eosinophilia often found in these reactions.

Introduction

Cutaneous reactions are among the most frequently observed adverse drug reactions. Most of these drug-induced exanthems can be described as erythematous or maculo-papular in nature (Bigby, 2001). However, drug allergies are known to be great imitators of diseases and can further encompass different clinical patterns like urticaria/angioedema, lichenoid or pustular skin eruptions, fixed drug eruptions, photosensitive reactions, vesicular bullous reactions, erythema exsudativum multiforme as well as rather severe reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis. Although the precise underlying pathomechanisms of many of these drug eruptions remain unknown, recent studies have improved our understanding how certain drugs may elicit distinct reactions like maculo-papular, bullous or pustular eruptions (Pichler, 2003). A large body of evidence obtained from immunohistological studies of skin lesions, as well as the generation and analysis of drug-specific T cell lines and T cell clones from allergic patients indicates that drug-specific T cells play a major role in these cutaneous drug eruptions (Pichler, 2003, Hertl and Merk, 1995). In the following the clinical, histological and immunohistological features as well as recent experimental data of maculo-papular exanthems (MPE) are presented.

Section snippets

Maculo-papular exanthems (MPE)

Erythematous or maculo-papular exanthems have been reported to account for approximately 95% of all drug-induced cutaneous eruptions (Bigby, 2001). Clinically, these exanthems usually appear as erythematous macular or papular eruptions which often start on the trunk and subsequently spread to the extremities in a symmetrical fashion (Fig. 1a). Lesions are often morbilliform, rubeliform or scarlatiniform and can mimic viral or bacterial exanthems. Furthermore, irregularly shaped annular and

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2017, Journal of Allergy and Clinical Immunology: In Practice
Patients can react to amoxicillin (AX) and clavulanic acid (CLV) taken in combination because of selective reactions to either drug. However, scant information exists concerning patients who react simultaneously to both compounds.
To analyze the mechanisms involved in 4 patients who developed allergic reactions to AX-CLV administration (3 with immediate IgE-mediated reaction and 1 with nonimmediate T-cell–mediated reaction) and who responded specifically to both AX and CLV.
Skin tests with benzylpenicillin (BP), AX, and CLV were done and, if necessary, drug provocation tests with BP/penicillin V, AX, and AX-CLV were carried out. In immediate reactors, serum specific IgE to benzylpenicilloyl and amoxicilloyl was determined by using the CAP-FEIA system (Pharmacia Diagnostics, Uppsala, Sweden), and basophil activation test to BP, AX, CLV, and AX-CLV was done. In nonimmediate reactors, immunohistochemistry of skin biopsy and analysis of dendritic cell maturation and T-cell–specific response to BP, AX, CLV, and AX-CLV at both acute and resolution phases of the reaction were conducted.
All patients with immediate reactions (N = 3) had good tolerance to BP and penicillin V. Two cases also had specific IgE to AX and all had a basophil activation test positive to AX, CLV, and AX-CLV. The patient with a nonimmediate reaction exhibited dendritic cell and T-lymphocyte responses specific to both AX and CLV. Finally, the analysis of the cells infiltrating the skin and peripheral blood during the acute phase indicated a T_H1 pattern response.
Our study provides evidence that reactions to both AX and CLV can appear in the same patient.
Adverse drug reactions and organ damage: The skin
2016, European Journal of Internal Medicine
Cutaneous adverse drug reactions are frequent, affecting 2–3% of hospitalized patients and in one twentieth of them are potentially life-threatening. Almost any pharmacologic agent can induce skin reactions, and certain drug classes, such as non-steroidal anti-inflammatory drugs, antibiotics and antiepileptics, have drug eruption rates ranging from 1% to 5%. Cutaneous drug reactions recognize several different pathomechanisms: some skin manifestations are immune-mediated like allergic reactions while others are the result of non immunological causes such as cumulative toxicity, photosensitivity, interaction with other drugs or different metabolic pathways. Cutaneous adverse drug reactions can be classified into two groups: common non-severe and rare life-threatening adverse drug reactions. Non-severe reactions are often exanthematous or urticarial whereas life-threatening reactions typically present with skin detachment or necrosis of large areas of the body and mucous membrane involvement, as in the Stevens–Johnson syndrome or toxic epidermal necrolysis. Clinicians should carefully evaluate the signs and symptoms of all cutaneous adverse drug reactions thought to be due to drugs and immediately discontinue drugs that are not essential. Short cycles of systemic corticosteroids in combination with antihistamines may be necessary for widespread exanthematous rashes, while more aggressive corticosteroid regimens or intravenous immunoglobulins associated with supportive treatment should be used for patients with Stevens–Johnson syndrome or toxic epidermal necrolysis.
Severe Cutaneous Drug Reactions: Do Overlapping Forms Exist?
2016, Actas Dermo-Sifiliograficas
Citation Excerpt :
Serious cutaneous drug reactions are immune-mediated events that are classed as unexpected adverse drug reactions. Immune-mediated hypersensitivity reactions vary according to the type of cutaneous drug reaction (Table 2).2,3 Thus, in urticarial drug reactions, type i IgE-mediated reactions are activated (Fig. 1) with a rapid clinical onset.
Acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms are all severe hypersensitivity reactions to medications. While each of these reactions is a well-established entity with specific diagnostic criteria, clinicians see cases that fulfill criteria for more than one form, prompting discussion on the possibility of combined forms. Such overlapping clinical pictures meeting the criteria for 2 conditions have thus become a topic of debate in dermatology in recent years. We describe 2 patients with cutaneous drug reactions having the characteristics of both acute generalized exanthematous pustulosis and Stevens-Johnson syndrome -toxic epidermal necrolysis. We also review previously published cases and current thinking on such overlapping conditions.
La pustulosis exantemática generalizada aguda, el síndrome de Stevens-Johnson, la necrólisis epidérmica tóxica y el síndrome de hipersensibilidad a fármacos con síntomas sistémicos y eosinofilia son reacciones de hipersensibilidad grave a fármacos. Aunque cada una de ellas se describe como una entidad bien constituida con criterios diagnósticos propios, en la práctica clínica se encuentran algunos casos que manifiestan características de 2 de estas entidades, abriendo el diálogo ante la posible existencia de formas combinadas. La existencia de estas formas solapadas entre 2 toxicodermias graves es motivo de controversia en los últimos años en diferentes foros de dermatología.
En el artículo se aportan 2 nuevos casos de formas solapadas entre pustulosis exantemática generalizada aguda y síndrome de Stevens-Johnson/necrólisis epidérmica tóxica, se revisan los casos previos publicados y el estado actual de esta controversia en la literatura.
Adverse Drug Reactions
2014, Handbook of Pharmacogenomics and Stratified Medicine
Adverse drug reactions (ADRs) are a major problem in clinical practice and drug development. Estimates suggest that they represent 6.5–6.7% of acute hospital admissions. ADRs represent the most common reason for drug withdrawal and the failure of new drugs to reach the market. They are commonly classified as type A (augmented) or type B (bizarre). Type A ADRs are predictable from the known pharmacology of the drug, and research has focused on genetic variation in drug metabolism pathways, such as cytochrome P450 enzymes, to explain the variation in ADR susceptibility. Success with this approach has been highlighted by the tailoring of azathioprine dosages according to thiopurine S-methyltransferase status. Type B ADRs are not predictable from the known pharmacology of the drug and include hypersensitivity reactions to antiepileptics and statin-induced myopathy. Several strong human leukocyte antigen (HLA) associations have been reported for type B ADRs, and testing for human leukocyte antigen B*57:01 is now routine prior to abacavir therapy. This chapter reviews the reported genetic associations with ADRs and explains their significance in clinical practice and the barriers to their clinical implementation.
Cutaneous Drug Reactions in the Pediatric Population
2014, Pediatric Clinics of North America
Citation Excerpt :
IVc: Perforins, granzyme-B, and Fas ligand are incriminated, activating cytotoxic T cells, natural killer (NK)/T cells, and NK cells clinically manifesting as contact dermatitis, maculopapular rash, and Stevens-Johnson syndrome (SJS)/toxic epidermal necrosis (TEN) exhanthems.9 In bullous exanthems there is a higher percentage of perforin-positive CD8+ killer T cells in the epidermis and dermis.10 IVd: CxCL8 and granulocyte macrophage colony-stimulating factor induce neutrophil activation, and can manifest on the skin as acute generalized exanthematic pustulosis (AGEP).
A review of cutaneous drug eruptions
2013, Clinics in Geriatric Medicine
Citation Excerpt :
The onset of the reaction typically occurs 1 to 2 weeks after the initiation of the causative medication.16,19 In cases of medication rechallenge, however, the drug eruption may present within a much shorter time frame; the eruptions may even present after the discontinuation of the drug.16,17,19,20 Certain drugs are more likely to evoke a morbilliform eruption.

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Drug-induced exanthems

Abstract

Introduction

Section snippets

Maculo-papular exanthems (MPE)

J. Invest. Dermatol.

J. Invest Dermatol.

J. Allerg. Clin. Immunol.

Blood Cells Mol. Dis.

J. Invest. Dermatol.

J. Allerg. Clin. Immunol.

Immunocompetent cells and adhesion molecules in 14 cases of cutaneous drug reactions induced with the use of antibiotics

Arch. Dermatol.

Up-regulated perforin expression of CD8+ blood lymphocytes in generalized non-anaphylactic drug eruptions and exacerbated psoriasis

Eur. J. Dermatol.

Expression of the skin-homing receptor in peripheral blood lymphocytes from subjects with non-immediate cutaneous allergic drug reactions

Allergy